The use of desferrithiocin analogs for iron clearing has been described by Bergeron, et al in “Desazadesmethyldesferrithiocin Analogues as Orally Effective Iron Chelators,” J. Med. Chem., vol. 42, no. 1, 95-108 (1999). Desferrithiocin and related compounds represent an advance in iron chelation therapy for subjects suffering from iron overload disorders. Present therapeutic agents, such as desferroxamine, require parenteral administration and have a very short half-life in the body, so that patient compliance and treatment cost are serious problems for subjects receiving long-term chelation therapy. Desferrithiocin and related compounds are effective when orally administered, thereby reducing patient compliance issues.
The iron clearing efficiency of desferrithiocin analogues has been shown to substantially depend on the stereochemistry at the C-4 position of the thiazoline ring. Desferrithiocin analogues based on (S)-enantiomers have been found to be especially active iron clearing agents in primates. See, for example, Bergeron, et al., “Effects of C-4 Stereochemistry and C-4′ Hydroxylation on the Iron Clearing Efficiency and Toxicity of Desferrithiocin Analogues,” J. Med. Chem., vol. 42, no. 13, 2432-2440 (1999).
(S)-Desferrithiocin analogues have been synthesized using the amino acid reagent D-cysteine, which is expensive compared to the naturally occurring L-cysteine isomer. U.S. Pat. Nos. 6,083,966 and 5,840,739, the entire teachings of which are incorporated by reference herein, describe thiazoline acid derivatives including those synthesized from D-cysteine.
Therefore, there is a need for novel methods of producing desferrithiocin analogues at a reasonable cost, and also for means of isolating desired enantiomers. In particular, there is a need for novel methods of producing the iron clearing compound 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid at a reasonable cost.